The present invention relates generally to the fields of tissue malfunction remedies. More particularly, it concerns application of a new nitric oxide-generating mixture to accelerate tissue healing or reduce undesired tissue contractions.
The biological importance of NO is well documented (Lancaster, 1996; Vincent, 1995; Moncada et al., 1992-1994; Feelisch and Stamler, 1996; Williams, 1996; Butler and Williams 1993; Ignarro and Murad, 1995). In mammals, NO is an endogenous physiological mediator of many biological functions. In addition, it is applied pharmacologically in various forms usually referred to as NO donors (nitroglycerin, sodium nitroprusside, etc.) to correct NO deficient states or to regulate the activities of many tissues (see appended list). Topical applications may be used to help wound and bum healing, hair growth, impotence, and cause vasodilatation where needed (e.g., ripening of the cervix in pregnancy). Local higher concentrations of NO (eye, skin, e.g.) are tolerated. Smith et al. (U.S. Pat. No. 5,519,020) describe polymeric nitric oxide sources thought to be useful to promote healing.
Two types of NO synthases (inducible and constitutive) produce NO in living organisms from L-arginine. Synthetic NO donors are also of two different types: those that evolve spontaneously NO as such from chemical precursors (Keefer et al., 1994; Keefer et al., 1993, U.S. Pat. No. 5,212,204; Hansen et al., 1992; Keefer et al., 1996; Garfield et al., 1995, U.S. patent application Ser. No. 08/440,970) or from solutions in suitable solvents (Garfield et al., 1996, U.S. patent application Ser. No. 08/633,337), and those that need metabolic redox processes for releasing NO (usually from higher oxidation states). Among the latter ones, organic nitrates (glycerol trinitrate (trivially known as nitroglycerin), isosorbide dinitrate or organic nitrites have been long used in medicine but they are known to produce tolerance, i.e., the need to progressively increase the dose in order to obtain a constant effect. These are also known to produce undesirable systemic side effects (e.g., headache).
Colorless gaseous NO (under some conditions) may react rapidly with atmospheric oxygen, yielding nitrogen dioxide (NO.sub.2), a red-brown gas with much higher toxicity than NO. However, at very low concentrations (up to 0.1 parts per million in air), NO may be administered to humans having breathing problems and have beneficial effects due to its bronchodilatory and vasodilatory activity. The reason why the reaction rate of NO with oxygen is very low at minute concentrations is related to the fact that the square of the NO concentration enters the expression of the reaction rate, according to the stoichiometry (eq. 1): EQU 2NO+0.sub.2 .fwdarw.2NO.sub.2 (1)
Nitrous acid (pK.sub.a =3.37) is produced from inorganic nitrites on treatment with acids (HA) of higher or comparable strength; in the literature, hydrochloric acid is described for this purpose (Feelisch and Stamler, 1996). Nitrous acid is stable in aqueous solution at low temperature, but it decomposes into NO and NO.sub.2 readily at room temperature according to the equations (2) and (3): EQU 2HA+2NaNO.sub.2 .fwdarw.2HNO.sub.2+ 2NaA (2) EQU 2HNO.sub.2 .fwdarw.NO+NO.sub.2 +H.sub.2 O (3)
There is, under the current U.S. Department of Agriculture regulations, the specification that for curing meat (especially ham and canned meat) and imparting a pink color to it, sodium nitrite must be used in combination with reducing agents such as ascorbate, erythrobate, or .alpha.-tocopherol (USDA Federal Registry, 1978; Mirvish, Appl. Pharmacol., 1975; Comforth, 1996). Also, the literature specifies that sodium ascorbate has a beneficial effect, again for use in meat products (Reith and Szakali, 1967). It is conjectured that nitric oxide is the active agent in these meat-curing processes, and that the color is due to the binding of nitric oxide to myoglobin. However, the above-mentioned uses antedate considerably the discovery of NO as an important physiological mediator, and until now the methods and procedures selected by the inventors are not described as a means for topical delivery of nitric oxide. Uses and Potential Uses of Nitric Oxide (NO) include
Cardiovascular: hypertension; angina; atherosclerosis; preeclampsia (pregnancy induced hypertension; toxemia; eclampsia; HELP syndrome; regulation of vascular conductance; regulation of blood flow; regulation of blood pressure; and myocardial ischemia.
Gastrointestinal: altered motility; and pyloric stenosis.
Lung Function: asthma; treatment of premature babies to increase lung function; and pulmonary hypertension.
Inflammation: autoimmune and immune diseases; acute inflammation; arthritis; resistance to infection; cancer; SLE-Lupus; anaphylactic reactions; and allograft rejection.
Central Nervous System: behavior; epilepsy; Alzheimer's disease; stroke; and growth hormone disorders (e.g., acromegaly).
Pancreas: diabetes.
Female Reproductive System or problems: ovulation; implantation/in vitro fertilization; premenstrual syndrome; dysmenorrhea; uterine contractile disorders; premature labor; cervical dilation; contraception; menopause symptoms; osteoporosis; endocrine disorders; and hormone replacement therapy.
Male Reproductive Problems: impotence; penile erection; male menopause symptoms; endocrine disorders; osteoporosis; and prostate hypertrophy.
Bladder and Kidney Problems: incontinence; renal arterial stenosis; and hypertension.
Dermatological Problems: eczema (skin reaction to foreign particle); autoimmune skin diseases; topical hair loss; acne; wounds; and burns.
The present invention includes formulations and methods for treating many, if not all, of these problems.